The purpose of the Emory CCPDER is to perform cutting-edge collaborative research on PD pathogenesis, with a focus on gene-environment interactions. The CCPDER brings together 3 established investigators - Drs. Greenamyre, Levey and Miller - who are each individually interested in the pathogenesis of PD and the roles that gene-environment interactions play in this disorder. Drs. Greenamyre and Levey bring both clinical and basic research perspectives to the Center. Dr. Miller brings an environmental toxicologist's point of view to the group. The proposed research will take place under the auspices of the new Center for Neurodegenerative Diseases (CND) in the recently completed Whitehead Research Building, where the investigators will share contiguous lab space and core equipment and facilities. The Emory CCPDER will capitalize on the expertise of each individual project leader in a truly collaborative, multidisciplinary endeavor in which the investigators will literally interact on a daily basis. The CCPDER consists of 3 integrative research projects supported by a Research Development Core. There are no Scientific Cores because the CND was conceived as a facility that would contain most necessary core facilities within its walls, with free access to all facilities by all CND investigators. Project 1 expands the rotenone model of PD into mice and organotypic slice cultures in order to examine geneenvironment interactions in this model. It will also screen other similar pesticides for their ability to cause PD, and it will screen neuroprotective strategies. Project 2 examines the vesicular monoamine transporter (VMAT2) as a target of environmental toxicants, such as organochlorines. Genetic approaches will be used to manipulate VMAT2 and examine its interactions with genes important in PD pathogenesis, such as alpha-synuclein. Project 3 is a genetic and pathological study of a new genetic linkage to PD, PARK10, which has been associated with increased risk of 'sporadic' PD in Iceland. Sporadic PD patients will be evaluated at Emory and high-density genome scans will be performed. Candidate genes have been identified and antibodies raised to the gene products. These will be assessed in human postmortem brain specimens and in experimental models of PD. The projects and administrative core involve molecular neurobiology, human genetics, clinical research, education, and collaboration with a PD epidemiologist. Common themes of the interactive projects include pesticides, gene-environment interactions, the ubiquitin/proteasome system, and dopamine. Each of the projects capitalizes on one or more existing funded projects. This fact, together with the core facilities of the CND allows us to leverage the requested funds for maximal effect.